Substituent dependent regioselective synthesis of pyranopyrandiones and 1,2-teraryls from 2H-pyran-2-ones

Article abstract of DOI:10.1016/j.tetlet.2005.05.084

The one-pot substituent-directed regioselective synthesis of 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 3 as the major and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles 4 as the minor products has been delineated through ring transformation of suitably functionalized 2H-pyran-2-ones 1 with aryl acetones 2. Under similar reaction conditions, 6-aryl-4-sec-amino-2H-pyran-2-ones 5 led, regioselectively, to 3,4-diaryl-2-methyl-6-sec-aminobenzonitriles 6.

Full text of DOI:10.1016/j.tetlet.2005.05.084

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5025–5027
Substituent dependent regioselective synthesis of
pyranopyrandiones and 1,2-teraryls from 2H-pyran-2-ones
I
Ramendra Pratap, Diptesh Sil and Vishnu Ji Ram*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 21 February 2005; revised 12 May 2005; accepted 19 May 2005
Available online 9 June 2005
Abstract—The one-pot substituent-directed regioselective synthesis of 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 3
as the major and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles 4 as the minor products has been delineated through ring trans-
formation of suitably functionalized 2H-pyran-2-ones 1 with aryl acetones 2. Under similar reaction conditions, 6-aryl-4-sec-amino-
2H-pyran-2-ones 5 led, regioselectively, to 3,4-diaryl-2-methyl-6-sec-aminobenzonitriles 6.
Ó 2005 Elsevier Ltd. All rights reserved.
3
A literature survey on the chemistry of pyranopyrandi-
ones and 1,2-teraryls revealed that compounds of both
ring systems have been meagerly explored. The basic
skeleton of pyranopyrandiones is present as a subunit
in various natural and synthetic products, for example,
I and II, of therapeutic importance and display antican-
one II was obtained from the reaction of 3-
methoxyphenol and diethyl ethoxymethylenemalonate,
albeit in poor yield.
The only structural commonality found in compounds
of types I and II is the benzopyran moiety, but they dif-
fer in their site of fusion with the other pyranone ring.
1
,2
3
cer
also exhibit photochemical
properties.
and antibacterial activities. These compounds
4
and luminescence
5
The chemistry of pyrano[3,4-c]pyran-4,5-diones is lar-
gely unexplored. Except for MO calculations, that is,
correlation of delocalization energy, p-bond order and
p-charge density of 20 different theoretical pyranopyran-
OCH3
OH
6
OH
diones including pyrano[3,4-c]pyran-4,5-dione III, no
O
O
other additional information is available in the litera-
ture. This has inspired us to develop an innovative route
for the construction of this class of compounds in order
to explore their therapeutic potential.
O
O
O
O
O
O
O
O
H CO
O
O
3
HO
I
II
III
OH
The wide-ranging applications of 1,2-teraryls as liquid
7
8
9
crystals, laser dyes, conducting polymers, textile dye
0
1
11
carriers, and dihydroortate dehydrogenase inhibitors
have also prompted us to develop a regioselective syn-
thesis of 1,2-teraryls.
The natural product I, meshimakobnol, has been
isolated from the fruit body of Phellinus linteus and pos-
1
Here, we report a one-pot regioselective synthesis of
H,5H-pyrano[3,4-c]pyran-4,5-diones 3 and 3,4-diaryl-
-methyl-6-sec-aminobenzonitriles 6 via base-catalyzed
sesses anticancer activity. The synthetic pyranopyrandi-
4
2
ring transformation of 6-aryl-4-methylsulfanyl-2H-pyr-
an-2-one-3-carbonitriles 1 and 6-aryl-4-sec-amino-2H-
pyran-2-one-3-carbonitriles 5 with aryl acetones 2. The
precursors 1 used for the synthesis of pyrano[3,4-c]-
Keywords: Pyranopyrandiones; 1,2-Teraryls; 2H-Pyran-2-ones.
q
CDRI communication No. 6723.
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
623405; e-mail: vjiram@yahoo.com
*
1
2
2
4,5-diones 3 were prepared via the reaction of aryl
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.084

5026
R. Pratap et al. / Tetrahedron Letters 46 (2005) 5025–5027
methyl ketones and methyl 3,3-dimethylthio-2-cyanoac-
rylate. The 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbo-
nitriles 5 were obtained by refluxing a mixture of
compounds 1 with various sec-amines in ethanol for
SCH3
CN
1
3
Ar'CH COCH
+
2
3
Ar
O
O
2
5
h. The precursor 2H-pyran-2-ones 1 are endowed with
1
1
a
Ar
2
a
Ar'
4-F.C H4
three electrophilic centres C2, C4 and C6 in which the
latter is highly prone to nucleophilic attack due to the
extended conjugation and the presence of an electron
withdrawing cyano substituent at position 3 of the pyran
ring while the C4 electrophilic centre is susceptible to
soft nucleophiles. In this reaction, the carbanion formed
from the aryl acetone acts as a nucleophile and preferen-
tially attacks at C4 of the pyran ring to form, initially, a
substitution product which undergoes cyclization under
basic conditions to give pyrano[3,4-c]pyran-4,5-diones 3
as the major products. We have been able to isolate
other minor compounds, characterized as the 3,4-di-
aryl-2-methyl-6-methylsulfanylbenzonitriles 4 resulting
from attack of the carbanion generated from the aryl
acetone 2 at position C6 of the pyran ring with cycliza-
tion followed by ring opening (Scheme 1). The products
C H
6
6
5
b 4-F.C H4
b 3-CF
.C H
6
3 6 4
c
d
e
4-Cl.C H4
c 2, 4-(CH O) .C H
6
3
2
6
3
4
4
-Br.C H4
6
-CH .C H
3
6 4
f
4-CH O.C H
3 6 4
g 2-thienyl
Path A
Path B
O
Ar'
CHCOCH
3
H CS
_
N
3
H CS
O
CN
O
3
Ar
O
O
Ar
Ar'
CH3
H
Ar'
O
C
O
O
CN
C N
H CS
O
OH
3
with high R values were characterized as 3,4-diaryl-2-
f
CH3
Ar
O
methyl-6-methylsulfanylbenzonitriles 4 and those with
low Rf values were characterized as 1,7-diaryl-2-
methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 3. Finally,
their structures were confirmed by spectroscopic studies.
Ar
Ar' H
CH3
SCH3
Ar'
Ar
O
CN
The poor yields and numerous commercial applications
of 1,2-teraryls prompted us to develop a regioselective
synthesis. The objective was achieved simply by chang-
ing the methylsulfanyl substituent, which is a good leav-
ing group, at position 4 of the pyran ring 1 and replacing
it with a sec-amino group. The substituent changed the
electrophilicity of the C4 and C6 positions of the pyran
ring resulting in the observed regioselectivity.
NH
O
O
Ar
CH3
Ar'
H O
2
4
CH3
Ar'
Ar
O
O
O
O
Thus, an equimolar mixture of 6-aryl-4-sec-amino-2H-
pyran-2-one-3-carbonitrile 5, aryl acetone 2 and pow-
dered KOH in dry DMF was stirred for 24 h at room
temperature and thereafter poured onto ice water with
vigorous stirring. Neutralization of the alkaline aqueous
solution with 10% HCl provided a precipitate which was
filtered, washed with water and finally dried under vac-
uum. The crude product was purified by silica gel col-
umn chromatography (Scheme 2).
3
Yield (%)
3
/4 Ar
Ar'
3
4
a
C6H5
4-F.C H4
3-CF .C H
60
73
19
9
6
b C H5
6
3
6 4
c
C
6
H
5
2,4-(CH O) .C H 73
11
21
16
21
16
18
18
21
13
15
3
2
6 3
d 4-F.C H
4-F.C H4
6
4-F.C H4
3-CF .C H
3-CF .C H
3 6
6
4-F.C H4
4-F.C H4
4-F.C H4
3-CF .C H
70
73
64
71
68
71
60
69
6
4
6
4
4
4
4
-Cl.C H
e
f
g
h
i
6
4
-Cl.C H4
6
3 6 4
-Br.C H4
6
4
6
-Br.C H4
1
The H NMR spectrum of 3l showed two singlets at d
2.15 and 6.00 for the CH and aromatic methine pro-
tons, respectively. The IR spectrum showed two car-
bonyl peaks at 1707 and 1772 cm . In the H NM R
spectrum of 4l, three singlets at d 2.29, 2.60 and 6.71
were attributed to CH , SCH and the aromatic methine
4-CH .C H
3
6
4
6
j
4-CH O.C H
3
6
4
4
6
3
k
4-CH O.C H
3
6
3
6
4
l
2-thienyl
6
4-F.C H4
À1
1
7
5
Scheme 1.
3
3
protons, respectively. The IR spectrum of 4l showed the
presence of a characteristic CN peak at 2211 cm
À1
.
the pyran ring with formation of a substitution product
as an intermediate, which undergoes cyclization involv-
ing the CN group and enolic OH under basic conditions
followed by hydrolysis to yield 3 as the major product.
The absence of nitrogen in microanalyses was consistent
with the assigned structure.
All the compounds synthesized were characterized by
spectroscopic and elemental analyses. Data for represen-
tative compounds are included.
1
4
A plausible mechanism involved in the formation of
products 3 and 4 is depicted in Scheme 1. The first step
in the formation of 3 is the attack of the carbanion
formed from the aryl acetone in situ at position 4 of
In the case of the formation of 4, the carbanion attacks
at C6 of the pyran ring with cyclization followed by ring

R. Pratap et al. / Tetrahedron Letters 46 (2005) 5025–5027
5027
NR2
CH
2
COCH
3
6. Creak, G. A.; Lewis, S. E.; Tan, S. F. J. Singapore Nat.
Acad. Sci. 1973, 3, 223–226.
CN
O
7
. Gary, G. W.; Winsor, P. A. In Liquid Crystals and Plastic
Crystals; John Wiley and Sons: New York, 1974; Vol. 1.
. Schneider, D. J.; Landis, D. A.; Fleitz, P. A.; Seliskar, C.
J.; Kaufman, J. M.; Steppel, R. N. Laser Chem. 1991, 11,
+
1
+
R
2
NH
Ar
O
8
F
5
2
a
49–62.
. (a) Baker, K. N.; Fratini, A. V.; Resch, T.; Knachel, H. C.;
Adams, W. W.; Socci, E. P.; Farmer, B. L. Polymer 1993,
KOH/DMF
9
Ar
%
Yield
6
a
NR2
C H
87
85
79
8
80
85
6
5
34, 1571–1587; (b) Kern, W.; Heitz, W.; Wirth, H. O.
Macromol. Chem. 1961, 42, 177–188.
b 4-Cl.C H4
CN
6
c
d
e
4-CH .C H
3 6
4
2-thienyl
4-Br.C H4
4-CH O.C H
10. Basu, B.; Das, P.; Mosharef, Md.; Bhuiyan, H.; Jha, S.
Tetrahedron Lett. 2003, 44, 3817–3820.
11. Sutton, A. E.; Clardy, J. Tetrahedron Lett. 2001, 42, 547–
2
Ar
CH3
6
f
3
6 4
5
51.
1
2. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A.
J. Chem. Res. (S) 1991, 98–99; (b) Ram, V. J.; Verma, M.;
Hussaini, F. A.; Shoeb, A. Liebigs Ann. Chem. 1991, 1229–
6
a-d NR = 4-phenylpiperazin-1-yl
2
F
6
6e, f NR = Pyrrolidin-1-yl
2
1
231.
3. Pratap, R.; Ram, V. J.; Sil, D. Tetrahedron Lett. 2004, 45,
743–5745.
Scheme 2.
1
1
5
4. (a) General procedure for the synthesis of 1,7-diaryl-2-
methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 3 and 3,4-
diaryl-2-methyl-6-methylsulfanylbenzonitriles 4: A mix-
ture of 1 (1 mmol), aryl acetone 2 (1 mmol) and KOH
(84 mg 1.5 mmol) in dry DMF (10 mL) was stirred for
24 h at room temperature. The reaction mixture was
poured onto crushed ice with vigorous stirring and then
neutralized with 10% HCl. The precipitate obtained was
filtered, washed with water and finally purified on a silica
gel column using 0.5% and 5% ethyl acetate in hexane as
opening condensation–cyclization involving the CO
functionality and C3 of the pyran ring to yield 1,2-terar-
yls 4 as minor products. Changing the SCH substituent
to a sec-amino group exclusively yielded 3,4-diaryl-2-
methyl-6-sec-aminobenzonitriles 6.
3
Our procedure provides an easy access to the synthesis
of 4H,5H-pyrano[3,4-c]pyran-4,5-diones 3 in 60–75%
yields and 1,2-teraryls 4 in 9–21% yields, in one step,
using very simple reagents. A change of substituent from
eluent for 4 and 3, respectively. (3l) Yield 75%; mp
>
CH
(m, 4H, ArH), 7.44–7.46 (m, 1H, ArH), 7.54–7.62 (m, 1H,
ArH); IR (KBr) 1707 and 1772 cm (CO); MS m/z 355
1
250 °C; H NMR (CDCl , 200 MHz) d 2.15 (s, 3H,
3
3
), 6.0 (s, 1H, ArH), 7.06–7.13 (m, 1H, ArH), 7.20–7.26
SCH to a sec-amino group in 1 exclusively provided
3
amino substituted 1,2-teraryls 6. The work-up for this
reaction is very simple and the synthesis is very
economical.
À1
+
(
M +1); C19
4
H11FO S (354.04) Calcd: C, 64.40; H, 3.13.
Found: C, 64.46; H, 3.17. (4l) Yield 15%; mp 150–152 °C;
1
3 3
H NMR (CDCl , 200 MHz) d 2.29 (s, 3H, CH ), 2.60 (s,
3
7
1
H, SCH ), 6.71 (s, 1H, ArH), 6.84–6.88 (m, 1H, ArH),
.03–7.07 (m, 4H, ArH), 7.21–7.24 (m, 1H, ArH), 7.33 (s,
3
Acknowledgements
À1
+
H, ArH); IR (KBr) 2211 cm (CN); MS m/z 339 (M );
14FNS (339.06) Calcd: C, 67.23; H, 4.16; N, 4.13.
C
19
H
2
V.J.R. and R.P. thank the CSIR for financial support
while D. Sil is grateful for a CSIR Senior Research
Fellowship.
Found: C, 67.26; H, 4.19; N, 4.10. (b) General procedure
for the synthesis of 3,4-diaryl-2-methyl-6-sec-aminobenzo-
nitriles 6: A mixture of 5 (1 mmol), aryl acetone 2
(
(
1 mmol) and KOH (84 mg, 1.5 mmol) in dry DMF
10 mL) was stirred for 24 h at room temperature. The
References and notes
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precipitate obtained was filtered, washed with water and
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acetate in hexane as eluent. 6e: Yield 80%; mp 128–130 °C;
1
3 2
H NMR (CDCl , 200 MHz) d 2.01 (s, 4H, CH ), 2.29 (s,
3H, CH
7.00 (m, 6H, ArH), 7.27 (d, J = 7.9 Hz, 2H, ArH); IR
), 3.64 (br s, 4H, NCH ), 6.49 (s, 1H, ArH), 6.85–
3
2
4
5
À1
+
(KBr) 2201 cm
20BrFN (434.08) Calcd: C, 66.22; H, 4.63; N, 6.43.
Found: C, 66.26; H, 4.59; N, 6.50.
(CN); MS m/z 435 (M +1);
. Nikolov, P.; Petkov, I.; Markov, P. Z. Naturforsch. A:
Phys. Sci. 2000, 741–744.
C
24
H
2